Increased expression of graft intraepithelial T-Cell pro-inflammatory cytokines compared with native lung during episodes of acute rejection

Abstract

We have previously reported that T-cell pro-inflammatory cytokines in the airways are associated with acute lung transplant rejection. However, during acute rejection episodes, we found no significant differences in airway intraepithelial T cell pro-inflammatory cytokines from stable and rejecting patients due to broad cytokine variability between patient groups. To overcome this limitation, we hypothesized that there would be an increase in pro-inflammatory intraepithelial T-cells in the graft compared with native airway during acute rejection. Bronchial brushings from patients with stable graft function, evidence of acute rejection, bronchiolitis obliterans syndrome, infection, and healthy controls were stimulated and pro-inflammatory cytokines in intraepithelial T cells from graft and native airway were determined using multiparameter flow cytometry. There was a significant increase in intraepithelial T-cell interferon-γ and tumor necrosis factor (TNF)-α in the graft of patients with acute rejection compared with intraepithelial T cells obtained from the native airway, but no changes were noted among other patient groups. The increase in intraepithelial T-cell TNF-α was more pronounced the higher the acute rejection grade. The graft airway epithelium is enriched with T cells producing interferon-γ and TNF-α during acute graft rejection. Therapeutic targeting of these pro-inflammatory cytokines and improved monitoring using this assay may reduce acute lung transplant rejection.